Background
Gonadotropin-releasing hormone (GnRH) is a neurohormone central to initiation of the reproductive hormone cascade. Pulsatile secretion of GnRH from the hypothalamus is key in establishing and maintaining normal gonadal function. Failure of this release results in isolated GnRH deficiency that can be distinguished by partial or complete lack of GnRH–induced luteinizing hormone (LH) pulses, normalization with pulsatile GnRH replacement therapy, and otherwise normal hypothalamic-pituitary neuroanatomy and neurophysiology.
Clinicians and scientists have long been intrigued by the findings of olfactory disturbances and concomitant reproductive dysfunction. In 1856, Spanish pathologist Maestre de San Juan noted the association between the failure of testicular development and the absence of the olfactory bulbs. However, the syndrome comprising complete GnRH deficiency and lack of olfactory senses is named Kallmann syndrome (KS) after the American geneticist Kallmann.
In 1944, Kallmann, Schoenfeld, and Barrera were the first to identify a genetic basis to this disorder.
In 1954, de Morsier connected the syndrome of hypogonadism and anosmia with the abnormal development of the anterior portion of the brain.
KS is a rare disorder that occurs in both sexes. In contrast to KS, GnRH deficiency leading to hypogonadotropic hypogonadism with an intact sense of smell is termed idiopathic hypogonadotropic hypogonadism (IHH). IHH results from dysfunction of GnRH neurons that have developed and migrated properly, whereas KS is caused by defective migration of GnRH neurons to their proper position in the hypothalamus during fetal development.